Role In Traumatic Brain Injury Research Articles

Ruxolitinib, a promising therapeutic candidate for traumatic brain injury through maintaining the homeostasis of cathepsin B

Traumatic brain injury (TBI) is one of the main causes of death and disability in the world. Owing to the heterogeneity and complexity of TBI pathogenesis, there is still no specific drug. Our previous studies have proved the neuroprotective effect of Ruxolitinib (Ruxo) on TBI, but further are needed to explore the potent mechanisms and potential translational application. Compelling evidence indicates that Cathepsin B (CTSB) plays an important role in TBI. However, the relationships between Ruxo and CTSB upon TBI remain non-elucidated. In this study, we established a mouse model of moderate TBI to clarify it. The neurological deficit in the behavioral test was alleviated when Ruxo administrated at 6 h post-TBI. Additionally, Ruxo significantly reduced the lesion volume. As for the pathological process of acute phase, Ruxo remarkably reduced the expression of proteins associated with cell demise, neuroinflammation, and neurodegeneration. Then the expression and location of CTSB were detected respectively. We found that the expression of CTSB exhibits a transient decrease and then persistent increase following TBI. The distribution of CTSB, mainly located at NeuN-positive neurons was unchanged. Importantly, the dysregulation of CTSB expression was reversed with the treatment of Ruxo. The timepoint was chosen when CTSB decreased, to further analyze its change in the extracted organelles; and Ruxo maintained the homeostasis of it in sub-cellular. In summary, our results demonstrate that Ruxo plays neuroprotection through maintaining the homeostasis of CTSB, and will be a promising therapeutic candidate for TBI in clinic.

Mini-Review: Role of Drugs Affecting Renin-Angiotensin System (RAS) in Traumatic Brain Injury (TBI): What We Know and What We Should Know.

Traumatic brain injuries (TBIs) are among the most important clinical and research areas in neurosurgery, owing to their devastating effects and high prevalence. Over the last few decades, there has been increasing research on the complex pathophysiology of TBI and secondary injuries following TBI. A growing body of evidence has shown that the renin-angiotensin system (RAS), a well-known cardiovascular regulatory pathway, plays a role in TBI pathophysiology. Acknowledging these complex and poorly understood pathways and their role in TBI could help design new clinical trials involving drugs that alter the RAS network, most notably angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. This study aimed to briefly review the molecular, animal, and human studies on these drugs in TBI and provide a clear vision for researchers to fill knowledge gaps in the future.

Inhibiting phosphatase and actin regulator 1 expression is neuroprotective in the context of traumatic brain injury.

Studies have found that the phosphatase actin regulatory factor 1 expression can be related to stroke, but it remains unclear whether changes in phosphatase actin regulatory factor 1 expression also play a role in traumatic brain injury. In this study we found that, in a mouse model of traumatic brain injury induced by controlled cortical impact, phosphatase actin regulatory factor 1 expression is increased in endothelial cells, neurons, astrocytes, and microglia. When we overexpressed phosphatase actin regulatory factor 1 by injection an adeno-associated virus vector into the contused area in the traumatic brain injury mice, the water content of the brain tissue increased. However, when phosphatase actin regulatory factor 1 was knocked down, the water content decreased. We also found that inhibiting phosphatase actin regulatory factor 1 expression regulated the nuclear factor kappa B signaling pathway, decreased blood-brain barrier permeability, reduced aquaporin 4 and intercellular adhesion molecule 1 expression, inhibited neuroinflammation, and neuronal apoptosis, thereby improving neurological function. The findings from this study indicate that phosphatase actin regulatory factor 1 may be a potential therapeutic target for traumatic brain injury.

Nicotinamide mononucleotides alleviated neurological impairment via anti-neuroinflammation in traumatic brain injury.

Traumatic brain injury (TBI) is one of the main factors of death and disability in adults with a high incidence worldwide. Nervous system injury, as the most common and serious secondary injury after TBI, determines the prognosis of TBI patients. NAD+ has been confirmed to have neuroprotective effects in neurodegenerative diseases, but its role in TBI remains to be explored. In our study, nicotinamide mononucleotides (NMN), a direct precursor of NAD+, was used to explore the specific role of NAD+ in rats with TBI. Our results showed that NMN administration markedly attenuated histological damages, neuronal death, brain edema, and improved neurological and cognitive deficits in TBI rats. Moreover, NMN treatment significantly suppressed activated astrocytes and microglia after TBI, and further inhibited the expressions of inflammatory factor. Besides, RNA sequencing was used to access the differently expressed genes (DEGs) and their enriched (Kyoto Encyclopedia of Genes and Genomes) KEGG pathways between Sham, TBI, and TBI+NMN. We found that 1589 genes were significantly changed in TBI and 792 genes were reversed by NMN administration. For example, inflammatory factor CCL2, toll like receptors TLR2 and TLR4, proinflammatory cytokines IL-6, IL-11 and IL1rn which were activated after TBI and were decreased by NMN treatment. GO analysis also demonstrated that inflammatory response was the most significant biological process reversed by NMN treatment. Moreover, the reversed DEGs were typically enriched in NF-Kappa B signaling pathway, Jak-STAT signaling pathway and TNF signaling pathway. Taken together, our data showed that NMN alleviated neurological impairment via anti-neuroinflammation in traumatic brain injury and the mechanisms may involve TLR2/4-NF-κB signaling.

Lipocalin-2 Is a Key Regulator of Neuroinflammation in Secondary Traumatic and Ischemic Brain Injury.

Reactive glial cells are hallmarks of brain injury. However, whether these cells contribute to secondary inflammatory pathology and neurological deficits remains poorly understood. Lipocalin-2 (LCN2) has inflammatory and neurotoxic effects in various disease models; however, its pathogenic role in traumatic brain injury remains unknown. The aim of the present study was to investigate the expression of LCN2 and its role in neuroinflammation following brain injury. LCN2 expression was high in the mouse brain after controlled cortical impact (CCI) and photothrombotic stroke (PTS) injury. Brain levels of LCN2 mRNA and protein were also significantly higher in patients with chronic traumatic encephalopathy (CTE) than in normal subjects. RT-PCR and immunofluorescence analyses revealed that astrocytes were the major cellular source of LCN2 in the injured brain. Lcn2 deficiency or intracisternal injection of an LCN2 neutralizing antibody reduced CCI- and PTS-induced brain lesions, behavioral deficits, and neuroinflammation. Mechanistically, in cultured glial cells, recombinant LCN2 protein enhanced scratch injury-induced proinflammatory cytokine gene expression and inhibited Gdnf gene expression, whereas Lcn2 deficiency exerted opposite effects. Together, our results from CTE patients, rodent brain injury models, and cultured glial cells suggest that LCN2 mediates secondary damage response to traumatic and ischemic brain injury by promoting neuroinflammation and suppressing the expression of neurotropic factors.

POSTINJURY FECAL MICROBIOME TRANSPLANT DECREASES LESION SIZE AND NEUROINFLAMMATION IN TRAUMATIC BRAIN INJURY.

Background: Traumatic brain injury (TBI) is an underrecognized public health threat. The constitutive activation of microglia after TBI has been linked to long-term neurocognitive deficits and the progression of neurodegenerative disease. Evolving evidence indicates a critical role for the gut-brain axis in this process. Specifically, TBI has been shown to induce the depletion of commensal gut bacteria. The resulting gut dysbiosis is associated with neuroinflammation and disease. Hypothesis: We hypothesized that fecal microbiota transplantation would attenuate microglial activation and improve neuropathology after TBI. Methods: C57Bl/6 mice were subjected to severe TBI (n = 10) or sham injury (n = 10) via an open-head controlled cortical impact. The mice underwent fecal microbiota transplantation (FMT) or vehicle alone via oral gavage once weekly for 4 weeks after injury. At 59 days after TBI, mice underwent three-dimensional, contrast-enhanced magnetic resonance imaging. Following imaging, mice were killed, brains harvested at 60 DPI, and CD45+ cells isolated via florescence-activated cell sorting. cDNA libraries were prepared using the 10x Genomics Chromium Single Cell 3' Reagent kit followed by sequencing on a HiSeq4000 instrument, and computational analysis was performed. Results: Fecal microbiota transplantation resulted in a >marked reduction of ventriculomegaly (P < 0.002) and preservation of white matter connectivity at 59 days after TBI (P < 0.0001). In addition, microglia from FMT-treated mice significantly reduced inflammatory gene expression and enriched pathways involving the heat-shock response compared with mice treated with vehicle alone. Conclusions: We hypothesized that restoring gut microbial community structure via FMT would attenuate microglial activation and reduce neuropathology after TBI. Our data demonstrated significant preservation of cortical volume and white matter connectivity after an injury compared with mice treated with vehicle alone. This preservation of neuroanatomy after TBI was associated with a marked reduction in inflammatory gene expression within the microglia of FMT-treated mice. Microglia from FMT-treated mice enriched pathways in the heat-shock response, which is known to play a neuroprotective role in TBI and other neurodegenerative disease processes.

Activating toll-like receptor 4 after traumatic brain injury inhibits neuroinflammation and the accelerated development of seizures in rats

Toll-like receptor 4 (TLR4) signaling plays a detrimental role in traumatic brain injury (TBI) pathology. Pharmacologic or genetic inactivating TLR4 diminish TBI inflammation and neurological complications. Nonetheless, TLR4 priming alleviates TBI inflammation and seizure susceptibility. We investigated impact of postconditioning with TLR4 agonist monophosphoryl lipid A (MPL) on TBI neuroinflammation and epileptogenesis in rats. TBI was induced in temporo-parietal cortex of rats by Controlled Cortical Impact device. Then rats received a single dose (0.1 μg/rat) of MPL by intracerebroventricular injection. After 24 h, CCI-injured rats received intraperitoneal injection of pentylenetetrazole 35 mg/kg once every other day until acquisition of generalized seizures. The injury size, number of survived neurons, and brain protein level of TNF-α, TGF-β, IL-10, and arginase1 (Arg1) were determined. Astrocytes and macrophage/microglia activation/polarization was assessed by double immunostaining with anti GFAP/Arg1 or anti Iba1/Arg1 antibodies. The CCI-injured rats developed generalized seizures after 5.9 ± 1.3 pentylenetetrazole injections (p < 0.001, compared to 12.3 ± 1.4 injections for sham-operated rats). MPL treatment returned the accelerated rate of epileptogenesis in TBI state to the sham-operated level. MPL did not change damage volume but attenuated number of dead neurons (p < 0.01). MPL decreased TNF-α overexpression (6 h post-TBI p < 0.0001), upregulated expression of TGF-β (48 h post-TBI, p < 0.0001), and IL-10 (48 h post-TBI, p < 0.0001) but did not change Arg1 expression. GFAP/Arg1 and Iba1/Arg1 positive cells were detected in TBI area with no significant change following MPL administration. MPL administration after TBI reduces vulnerability to seizure acquisition through down regulating neural death and inflammation, and up-regulating anti-inflammatory cytokines. This capacity along with the clinical safety, makes MPL a potential candidate for development of drugs against neurological deficits of TBI.

MicroRNA-124/Death-Associated Protein Kinase 1 Signaling Regulates Neuronal Apoptosis in Traumatic Brain Injury via Phosphorylating NR2B.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine-protein kinase, promotes neurons apoptosis in ischemic stroke and Alzheimer’s disease (AD). We hypothesized that knockdown DAPK1 may play a protective role in traumatic brain injury (TBI) and explore underlying molecular mechanisms. ELISA, Western blotting, immunofluorescence, dual-luciferase assay, and Reverse Transcription and quantitative Polymerase Chain Reaction (RT-qPCR) were used to determine the mechanism for the role of DAPK1 in TBI. Open field and novel objective recognition tests examined motor and memory functions. The morphology and number of synapses were observed by transmission electron microscopy and Golgi staining. DAPK1 was mainly found in neurons and significantly increased in TBI patients and TBI mice. The dual-luciferase assay showed that DAPK1 was upregulated by miR-124 loss. The number of TUNEL+ cells, expression levels of cleaved caspase3 and p-NR2B/NR2B were significantly reduced after knocking-down DAPK1 or overexpressing miR-124 in TBI mice; and motor and memory dysfunction was recovered. After Tat-NR2B were injected in TBI mice, pathological and behavioral changes were mitigated while the morphology while the number of synapses were not affected. Overall, DAPK1 is a downstream target gene of miR-124 that regulates neuronal apoptosis in TBI mice via NR2B. What’s more, DAPK1 restores motor and memory dysfunctions without affecting the number and morphology of synapses.

Comprehensive RNA Expression Analysis Revealed Biological Functions of Key Gene Sets and Identified Disease-Associated Cell Types Involved in Rat Traumatic Brain Injury.

Traumatic brain injury (TBI) is a worldwide public health concern without major therapeutic breakthroughs over the past decades. Developing effective treatment options and improving the prognosis of TBI depends on a better understanding of the mechanisms underlying TBI. This study performed a comprehensive analysis of 15 RNA expression datasets of rat TBIs from the GEO database. By integrating the results from the various analyses, this study investigated the biological processes, pathways, and cell types associated with TBI and explored the activity of these cells during various TBI phases. The results showed the response to cytokine, inflammatory response, bacteria-associated response, metabolic and biosynthetic processes, and pathways of neurodegeneration to be involved in the pathogenesis of TBI. The cellular abundance of microglia, perivascular macrophages (PM), and neurons were found to differ after TBI and at different times postinjury. In conclusion, immune- and inflammation-related pathways, as well as pathways of neurodegeneration, are closely related to TBI. Microglia, PM, and neurons are thought to play roles in TBI with different activities that vary by phase of TBI.

Diagnostic and prognostic role of magnetic resonance imaging in cases of moderate to severe traumatic brain injury

Moderate to severe traumatic brain injury (TBI) remains a leading cause of death and disability worldwide. Timely diagnosis and accurate prognostication play a key role in informed clinical decision-making. Though magnetic resonance imaging (MRI) is a superior anatomical scan compared to computerized tomography (CT), the latter remains the current investigation of choice in the clinical setting of TBI due to some of the former’s inherent deficiencies in imaging bone/blood, limited access, cost, etc. Nevertheless, the fact that MRI is a valuable adjunct in evaluating the TBI patients with clinical findings disproportionate to the CT scan substantiates its possible complementary/supplementary diagnostic and prognostic role in TBI. MRI scan is ideally placed on demonstrating the shear/diffuse axonal injury (DAI), non-haemorrhagic intraparenchymal lesions, and brain stem lesions poorly delineated by a CT scan. The currently available literature demonstrates that DAI and caudal brainstem lesions are indicators of poorer outcomes. However, the prognostic value of MRI, in addition to that of CT, remains an area of active investigation. We have tried to present the evidence-based use of MRI in moderate to severe TBI. Advances in newer MRI sequences like susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), functional MRI (fMRI), and magnetic encephalography (MEG) have the potential to revolutionize the current role of MRI in TBI.

Advanced Neuroimaging Role in Traumatic Brain Injury: A Narrative Review.

Traumatic brain injury (TBI) is a common source of morbidity and mortality among civilians and military personnel. Initial routine neuroimaging plays an essential role in rapidly assessing intracranial injury that may require intervention. However, in the context of TBI, limitations of routine neuroimaging include poor visualization of more subtle changes of brain parenchymal after injury, poor prognostic ability and inability to analyze cerebral perfusion, metabolite and mechanical properties. With the development of modern neuroimaging techniques, advanced neuroimaging techniques have greatly boosted the studies in the diagnosis, prognostication, and eventually impacting treatment of TBI. Advances in neuroimaging techniques have shown potential, including (1) Ultrasound (US) based techniques (contrast-enhanced US, intravascular US, and US elastography), (2) Magnetic resonance imaging (MRI) based techniques (diffusion tensor imaging, magnetic resonance spectroscopy, perfusion weighted imaging, magnetic resonance elastography and functional MRI), and (3) molecular imaging based techniques (positron emission tomography and single photon emission computed tomography). Therefore, in this review, we aim to summarize the role of these advanced neuroimaging techniques in the evaluation and management of TBI. This review is the first to combine the role of the US, MRI and molecular imaging based techniques in TBI. Advanced neuroimaging techniques have great potential; still, there is much to improve. With more clinical validation and larger studies, these techniques will be likely applied for routine clinical use from the initial research.

Role of Bevacizumab on Vascular Endothelial Growth Factor in Apolipoprotein E Deficient Mice after Traumatic Brain Injury.

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB). Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI and to be overexpressed in the absence of apolipoprotein E (ApoE). Bevacizumab, a VEGF inhibitor, demonstrated neuroprotective activity in several models of TBI. However, the effects of bevacizumab on Apo-E deficient mice are not well studied. The present study aimed to evaluate VEGF expression and the effects of bevacizumab on BBB and neuroinflammation in ApoE−/− mice undergoing TBI. Furthermore, for the first time, this study evaluates the effects of bevacizumab on the long-term consequences of TBI, such as atherosclerosis. The results showed that motor deficits induced by controlled cortical impact (CCI) were accompanied by increased brain edema and VEGF expression. Treatment with bevacizumab significantly improved motor deficits and significantly decreased VEGF levels, as well as brain edema compared to the control group. Furthermore, the results showed that bevacizumab preserves the integrity of the BBB and reduces the neuroinflammation induced by TBI. Regarding the effects of bevacizumab on atherosclerosis, it was observed for the first time that its ability to modulate VEGF in the acute phase of head injury prevents the acceleration of atherosclerosis. Therefore, the present study demonstrates not only the neuroprotective activity of bevacizumab but also its action on the vascular consequences related to TBI.

Research Progress on the Inflammatory Effects of Long Non-coding RNA in Traumatic Brain Injury.

Globally, traumatic brain injury (TBI) is an acute clinical event and an important cause of death and long-term disability. However, the underlying mechanism of the pathophysiological has not been fully elucidated and the lack of effective treatment a huge burden to individuals, families, and society. Several studies have shown that long non-coding RNAs (lncRNAs) might play a crucial role in TBI; they are abundant in the central nervous system (CNS) and participate in a variety of pathophysiological processes, including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis, and neurogenesis. Some lncRNAs modulate multiple therapeutic targets after TBI, including inflammation, thus, these lncRNAs have tremendous therapeutic potential for TBI, as they are promising biomarkers for TBI diagnosis, treatment, and prognosis prediction. This review discusses the differential expression of different lncRNAs in brain tissue during TBI, which is likely related to the physiological and pathological processes involved in TBI. These findings may provide new targets for further scientific research on the molecular mechanisms of TBI and potential therapeutic interventions.

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Introduction:Psychosis is a relatively infrequent but potentially serious and debilitating consequence of traumatic brain injury However, the role of TBI in the Genesis of psychosis is a complex matter about which there is considerable scientific uncertainty and disagreement. Although the frequency of psychosis following TBI exceeds that of general (Davison & Bagley, 1969; Achte et al., 196population9; Achteet al., 1991),Case report:A 53years old male patient Mr. X studied till 10class, married, used to work in rice mill belonging to middle socio-economic status, hailing from urban background was accompanied to the OPD by his sister. Informant had complaints of head injury with LOC 8 months back (suspiciousness on wife abusing family members, Hearing of voices which are unexisted, abnormal behavior, and memory impairment since 6 months. Patient started suspecting his wife that she is having affair with neighbors and whenever his wife goes to bathroom and to outside for shop for basic needs he started to abuse her that she is having affair with neibours and when confronted by wife he used tell that 10 members male and female are discussing that she has affair with neighborhood person and they are telling him and then she started to abuse wife and son and used to beat without provocation which is associated with disturbed sleep and reduced appetite. Later he started to go away from home and went to sisters home for and complains to sister about wife that stranger was coming to meet his wife. Whenever they tried explaining that it is not true he used to quarrel with also this he also had memory disturbances. All the investigations were normal and he was started on Tab. Olanzepine5mg B. D and Tab. Lorazepam 2mg SOS and tab Bcomplex O. DDiscussion:The psychosis after traumatic brain injury occurs in 1% of all TBI’s Psychosis after traumatic brain injury (TBI) is a relatively uncommon condition that presents both clinical and conceptual challenges. DSM-5 criteria for Psychotic Disorder due to Another Medical Condition define psychotic disorder due to TBI as delusions or hallucinations that are direct physiologic consequences of TBI. Here, we present a patient with psychotic disorder following traumatic brain injury which was located in bilateral temporal lobes r and left lateral ventricle Considering the accurate temporal relationship between the brain trauma and following psychotic symptoms, we think that this case represents a smart sample of a patient with psychotic symptoms which were associated with traumatic brain injury. Following the accident, the patient had suffered a moderate cognitive impairment, and apparent behavioral changes Hence, evaluating this patient as Temporal lobe damage and accompanying psychotic disorder may be more rational. In conclusion, this report illustrates an interesting patient with post-traumatic psychosis in addition to other temporal disturbances which constitutes a demonstrative report for clinical concerns. Future reports of larger cases of these patients in association with brain lesions will add substantial insights for understanding the anatomical pathways underlying psychosis as well as other neurological disorders. These study results may also add new perspectives to the unknown aspects of the pathophysiology of primary psychosis, from a distinct point of view.Conclusion:Collaborative efforts are needed to continue support and research in this field in future, accommodating biter treatment and rehabilitative options to patients who suffer with TBi

Comprehensive analysis of circRNA expression profiles in rat cerebral cortex after moderate traumatic brain injury.

Traumatic brain injury is a medical event of global concern, and a growing body of research suggests that circular RNAs can play very important roles in traumatic brain injury. To explore the functions of more novel and valuable circular RNA in traumatic brain injury response, a moderate traumatic brain injury in rats was established and comprehensive analysis of circular RNA expression profiles in rat cerebral cortex was done. As a result, 301 up-regulated and 284 down-regulated circular RNAs were obtained in moderate traumatic brain injury rats, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed based on the circular RNA's host genes, and a circRNA-miRNA interaction network based on differentially expressed circular RNAs was constructed. Also, four circular RNAs were validated by RT-qPCR and Sanger sequencing. This study showed that differentially expressed circular RNAs existed between rat cerebral cortex after moderate traumatic brain injury and control. And this will provide valuable information for circular RNA research in the field of traumatic brain injury.

Benefits of vitamin D supplementation to attenuate TBI secondary injury?

Vitamin D supplementation has been shown to improve outcomes for patients suffering from a variety of illnesses such as stroke and cancer. Vitamin D deficiencies have been associated with longer hospital stays, greater severity of symptoms, and death in some complex cases. Due to vitamin D’s burgeoning role in improving patient outcomes, a new sector of research is focusing on the lesser-known implications of vitamin D on health. Traumatic brain injury (TBI) affects approximately 69 million people worldwide per year. Here, we summarize the current scientific understanding of vitamin D dynamics with TBI to elucidate a potential way to lessen the cascade of secondary damage after an initial insult, with the goal of improving overall patient outcomes. Because vitamin D supplementation has been correlated with better outcomes in other pathologies involving immune and inflammatory molecules, it is important to study the potential effect of vitamin D deficiency (VDD) and supplementation on TBI outcomes. Research on vitamin D supplementation in TBI remains in the preliminary stages. There is still much to learn about vitamin D deficiency, dosage, variants of supplementary forms, mechanisms, and its role in TBI.

MicroRNA-31 inhibits traumatic brain injury-triggered neuronal cell apoptosis by regulating hypoxia-inducible factor-1A/vascular endothelial growth factor A axis.

MicroRNAs are dysregulated in traumatic brain injury and are involved in neuronal cell behaviors. Previous studies identified miR-31 as a spinal cord injury-related microRNA, while its role in traumatic brain injury remains indistinct. Herein, we explored the participation of miR-31 in traumatic brain injury. Traumatic brain injury model was established after traumatic neuron injury. Neurocytes were transfected with miR-31 mimic or inhibitor. Cell counting kit-8, lactate dehydrogenase assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and western blot were applied to examine cell viability, lactate dehydrogenase releasing, apoptosis, and apoptosis-related protein. The binding between miR-31 and hypoxia-inducible factor-1A was verified by luciferase assay. Quantitative reverse transcription-PCR was used to detect the regulation of traumatic neuron injury or hypoxia-inducible factor-1A overexpression on vascular endothelial growth factor A level. The effects of hypoxia-inducible factor-1A or vascular endothelial growth factor A on neuronal cell injury were examined. Additionally, phosphatidylinositol 3kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway was also examined using western blot. Downregulation of miR-31 promoted traumatic neuron injury-induced neuronal cell injury, and its overexpression did the opposite. Hypoxia-inducible factor-1A acted as a downstream mRNA of miR-31 and its downregulation was involved in miR-31-regulated neuronal cell injury. Vascular endothelial growth factor A level was elevated by traumatic neuron injury or hypoxia-inducible factor-1A overexpression. Hypoxia-inducible factor-1A enhanced neuronal cell injury via promoting vascular endothelial growth factor A expression. Furthermore, miR-31/hypoxia-inducible factor-1A/vascular endothelial growth factor A regulated PI3K/AKT/mTOR pathway in neuronal cells. Our study demonstrated miR-31 inhibited neuronal cell apoptosis via regulating hypoxia-inducible factor-1A/vascular endothelial growth factor A axis.

WNK3 Promotes Neuronal Survival after Traumatic Brain Injury in Rats

With-no-lysine kinase 3 (WNK3) is a key regulator of chloride ion transport and neuronal survival in diverse cell types. WNK3 was previously found to regulate the activity of Na+-K+-2Cl− cotransporter-1 (NKCC1) in ischemia-associated brain damage. However, the role of WNK3 in traumatic brain injury (TBI) has not yet been studied. A weight-drop TBI model was established in Sprague-Dawley rats. Overexpression and specific inhibition were used to investigate the role of WNK3 in TBI via Western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses. We found pronounced TBI-induced downregulation of WNK3 expression and upregulation of NKCC1 expression in neurons, especially at 48 h. Overexpression of WNK3 significantly ameliorated neuronal apoptosis, blood–brain barrier (BBB) disruption, brain edema and neurological deficits at 48 h after TBI. These effects were concomitant with reductions in p-NKCC1 and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) expression. Furthermore, bumetanide administration enhanced the neuroprotective effects of WNK3 overexpression against brain injury. Thus, WNK3 plays a neuroprotective role in TBI, and overexpression of WNK3 may increase cell resistance to apoptotic insults and brain edema, thereby alleviating secondary brain injury.

Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury.

The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM. The Sig-1R is expressed broadly in cells of the central nervous system (CNS) and has been reported to be involved in various neurological disorders. Traumatic brain injury (TBI)-induced secondary injury involves complex and interrelated pathophysiological processes such as cellular apoptosis, glutamate excitotoxicity, inflammatory responses, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction. Thus, given the pluripotent modulation of the Sig-1R in diverse neurological disorders, we hypothesized that the Sig-1R may affect a series of pathophysiology after TBI. This review summarizes the current knowledge of the Sig-1R, its mechanistic role in various pathophysiological processes of multiple CNS diseases, and its potential therapeutic role in TBI.

RhFGF20 promotes angiogenesis and vascular repair following traumatic brain injury by regulating Wnt/β-catenin pathway

The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20 (FGF20) is a brain-derived neurotrophic factor, that has been shown to play an important role in the survival of dopaminergic neurons and the treatment of Parkinson's disease (PD). However, little is known about the role of FGF20 in the treatment of TBI and its underlying mechanism. The purpose of this study was to evaluate the protective effect of recombinant human FGF20 (rhFGF20) on protecting cerebral blood vessels after TBI. In this study, we indicated that rhFGF20 could reduce brain edema, Evans blue penetration and upregulated the expression of blood-brain barrier (BBB)-related tight junction (TJ) proteins, exerting a protective effect on the BBB in vivo after TBI. In the TBI repair phase, rhFGF20 promoted angiogenesis, neurological and cognitive function recovery. In tumor necrosis factor-α (TNF-α)-induced human brain microvascular endothelial cells (hCMEC/D3), an in vitro BBB disruption model, rhFGF20 reversed the impairment in cell migration and tube formation induced by TNF-α. Moreover, in both the TBI mouse model and the in vitro model, rhFGF20 increased the expression of β-catenin and GSK3β, which are the two key regulators in the Wnt/β-catenin signaling pathway. In addition, the Wnt/β-catenin inhibitor IWR-1-endo significantly reversed the effects of rhFGF20. These results indicate that rhFGF20 may prevent vascular repair and angiogenesis through the Wnt/β-catenin pathway.